Revumenib, Azacitidine, and Venetoclax for the Treatment of Patients with Newly Diagnosed KMT2A Translocated Acute Myeloid Leukemia, RAVEN Trial

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Age 18-65 years at the time of consent
• Untreated AML based on 2022 World Health Organization (WHO) or International Consensus Classification (ICC) criteria with KMT2A translocation by local standard diagnostic testing by cytogenetics/karyotype or fluorescence in situ hybridization (FISH)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) before the start of treatment (unless considered due to leukemic involvement and must be < 5 x ULN)
• Total bilirubin =< 1.5 x ULN (except for suspected or known Gilbert’s Syndrome) before the start of treatment
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, and 2
• Adequate renal function as defined by calculated creatinine clearance >= 30 mL/min from the local laboratory
• Females of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours prior to study treatment * NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 1 form of effective methods of contraception from the time of informed consent until 6 months following the last dose of azacitidine, 30 days after the last dose of venetoclax, or 4 months following the last dose of revumenib

Exclusion Criteria

• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 120 days after the last dose of study therapy
• Isolated myeloid sarcoma (patients must have blood or marrow involvement with AML to enter study)
• Active central nervous system (CNS) involvement by AML. Of note, patients are eligible if CNS leukemia is in remission at the time of study entry
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Previous treatment for AML other than hydroxyurea or leukapheresis
• Patients with corrected QT (QTc) Fridericia (QTcF) > 450 msec * Patients with right, left, or partial bundle branch blocks or pacemaker that may confound interpretation of this reading are excluded from this provided they lack history of primary arrhythmic events and are cleared by cardiology for enrollment in the trial. Any factors that increase the risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome
• Patients with FLT3-ITD mutations
• Patients with white blood cell (WBC) >= 20 x10^9/L. (Patients must have WBC < 20 x 10^9/L to begin therapy and hydroxyurea may be used to obtain this level)
• Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial
• Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection. Patients may be eligible if these infections are well controlled
• Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction as presentation of AML, New York Heart Association (NYHA) Class >= III heart failure (New York Heart Association [NYHA] Classification), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled
• Prior history of transient ischemic attack (TIA) or stroke within last 6 months of enrollment
• Cirrhosis with Child-Pugh Score of B or C or National Cancer Institute (NCI) Organ Dysfunction Working Group category of severe dysfunction
• Inability to swallow oral medications or any gastrointestinal pathology likely to affect oral drug absorption or ingestion (ie, gastric bypass, gastroparesis, etc)
• As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control
• Patients who have received an investigational agent (for any indication with the exception of AML) within 5 half- lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half- life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA)